Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

Samur, Mehmet K.; Fulciniti, Mariateresa; Samur, Anıl Aktaş; Bazarbachi, Abdul-Hamid; Tai, Yu‐Tzu; Prabhala, Rao; Alonso, Anselmo; Sperling, Adam S.; Campbell, Timothy B.; Petrocca, Fabio; Hege, Kristen; Kaiser, Shari M.; Loiseau, Hervé Avet; Anderson, Kenneth C.; Munshi, Nikhil C.

doi:10.1038/s41467-021-21177-5

Cited by 232 publications

(169 citation statements)

References 31 publications

(36 reference statements)

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“…Specifically, it has been observed that for BCMA-targeting agents, antigen deregulation could happen as a consequence of previous anti-BCMA treatments (e.g., belantamab) or by genetic alterations. Indeed, biallelic loss of BCMA has been reported in several patients relapsing after anti-BCMA CAR-T [80,81]. Additionally, after a deeper analysis, a heterozygous TNFRSF17 loss or monosomy of 16 in about 15% of MM patients never exposed to anti-BCMA therapy has been observed, letting us hypothesize a role for genomic alteration in the development of resistance to BCMAtargeting treatments [80,81].…”

Section: Long-term Failure Of Novel Immunotherapies: Pitfalls and Opportunitiesmentioning

confidence: 92%

“…Indeed, biallelic loss of BCMA has been reported in several patients relapsing after anti-BCMA CAR-T [80,81]. Additionally, after a deeper analysis, a heterozygous TNFRSF17 loss or monosomy of 16 in about 15% of MM patients never exposed to anti-BCMA therapy has been observed, letting us hypothesize a role for genomic alteration in the development of resistance to BCMAtargeting treatments [80,81]. On the other hand, the activity of anti-CD3/BCMA bispecific antibodies have been found to be completely abrogated by the presence of granulocyte-like MDSC [16] or dysfunctional/exhausted T-cells, which arise under an immunosuppressive microenvironment characterized by a repeated T-cell stimulation [79].…”

Section: Long-term Failure Of Novel Immunotherapies: Pitfalls and Opportunitiesmentioning

confidence: 99%

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Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Botta

Mendicino

Martino

et al. 2021

Cancers

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Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients.

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Section: Long-term Failure Of Novel Immunotherapies: Pitfalls and Opportunitiesmentioning

confidence: 92%

Section: Long-term Failure Of Novel Immunotherapies: Pitfalls and Opportunitiesmentioning

confidence: 99%

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Botta

Mendicino

Martino

et al. 2021

Cancers

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“…The mechanism whereby BCMA CAR T cells reduce BCMA cell-surface expression levels probably includes selection of cells with lower BCMA levels, whereas tumor cells with higher BCMA expression are eliminated. Furthermore, biallelic BCMA deletions, resulting in lack of BCMA expression, have also recently been found to trigger resistance to BCMA CAR T cells (27)(28)(29). Although BCMA antigen loss seems to be an uncommon mechanism of escape from BCMA-directed CAR T-cell therapy (4% in the KarMMa study; ref.…”

Section: Tumor-related Resistance Mechanisms (Soluble) Bcmamentioning

confidence: 99%

“…Although BCMA antigen loss seems to be an uncommon mechanism of escape from BCMA-directed CAR T-cell therapy (4% in the KarMMa study; ref. 10), it may have major therapeutic implications because biallelic loss of BCMA will also confer resistance to retreatment with similar or other BCMA-targeted therapies (28). This highlights the need to examine for BCMA gene alterations or to assess BCMA expression when treatment with another BCMA-directed immunotherapy is considered.…”

Section: Tumor-related Resistance Mechanisms (Soluble) Bcmamentioning

confidence: 99%

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Donk

Themeli

Usmani

2021

Blood Cancer Discovery

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B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells have substantial therapeutic potential in multiple myeloma (MM), but most patients eventually relapse. Determinants of response and mechanisms of resistance are most likely multifactorial and include MM-related factors, premanufacturing T-cell characteristics, CAR T-cell-related features, and several components of the immunosuppressive microenvironment. Efforts to improve the potency and safety of CAR T-cell therapy include optimizing CAR design, combinatorial approaches to enhance persistence and activity, treatment of less heavily pretreated patients, and dual-antigen targeting to prevent antigen escape. We expect that these rationally designed strategies will contribute to further improvement in the clinical outcome of patients with MM.Significance: Although BCMA-specific CAR T-cell therapies are highly effective in heavily pretreated patients with MM, there has been, until now, no indication of a plateau in the survival curves. In this review, we provide an overview of the determinants of response and the mechanisms that contribute to the development of treatment failure after initial remission (acquired resistance). A better understanding of these mechanisms, underlying lack of disease response, and acquired resistance may lead to further improvements in the effectiveness of CAR T-cell therapy. iNtRODUctiONAlthough the introduction of new anti-multiple myeloma (MM) agents has markedly improved the survival of patients with MM, there is an unmet need for new drugs for patients who develop resistance to immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and CD38-targeting antibodies (triple-class refractory disease), which carries a poor prognosis (1). Also, newly diagnosed patients with high-risk disease [e.g., presence of del(17p), t(4;14), or t(14;16)] or suboptimal response have an impaired outcome, and these patients may benefit from the incorporation of new drugs with novel mechanisms of action in first-line regimens.A promising new strategy is the reprogramming of T cells to target MM cells by introducing genes encoding chimeric antigen receptors (CAR). CARs are fusion proteins, combining an antigen-recognition moiety [commonly a monoclonal antibody-derived single-chain variable fragment (scFv), but other formats such as natural ligands are also possible; ref.2] with a T-cell activation domain, typically CD3ζ. These two parts are connected via an extracellular spacer region (hinge) and a transmembrane-spanning element. Second-generation CARs incorporating a costimulatory domain, such as CD28, 4-1BB, OX40, or ICOS, into the CAR endodomain result in enhanced antitumor activity of the modified T cells compared with first-generation CARs without such domain (Fig. 1; ref. 3). Importantly, CAR T cells eliminate tumor cells in a non-major histocompatibility complex (MHC)restricted manner.Most CAR T-cell products, currently evaluated in clinical trials for patients with MM, target B-cell maturation antigen (BCMA), which is...

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“…61 A similar case of homozygous loss of BCMA expression has been reported in a patient in the phase I CRB-401 trial who was unsuccessfully treated at relapse, 9 months after the first infusion. 62 Although homozygous loss of BCMA genes is extremely rare, the 16p monosomy, leading to a heterozygous BCMA-deficient phenotype is relatively common and it has been suggested that it may be a mechanism leading to resistance to anti-BCMA therapies. 61 At the time of analysis, OS was immature, with 66% of patients still censored, 78% of patients were alive at 12 months, and the estimated median OS was 19.4 months [95% confidence interval (CI), 18.2–non-evaluable].…”

Section: Idecabtagene Vicleucel Developmentmentioning

confidence: 99%

The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

Oriol

Abril

Torrent

et al. 2021

Therapeutic Advances in Hematology

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The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

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Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

Cited by 232 publications

References 31 publications

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

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